Polymersome nanoreactors with tumor pH-triggered selective membrane permeability for prodrug delivery, activation, and combined oxidation-chemotherapy

J Control Release. 2019 Jun 10:303:209-222. doi: 10.1016/j.jconrel.2019.04.032. Epub 2019 Apr 23.


Therapeutic nanoreactors are currently emerging as promising nanoplatforms to in situ transform inert prodrugs into active drugs. Nevertheless, it is still challenging to engineer a nanoreactor with balanced key features of tunable selective membrane permeability and structural stability for prodrug delivery and activation in diseased tissues. Herein, we present a facile strategy to engineer a polymersome nanoreactor with tumor-specific tunable membrane permeability to load both hydrophobic phenylboronic ester-caged anticancer prodrugs (e.g., camptothecin or paclitaxel prodrug) and hydrophilic glucose oxidase (GOD) in the membranes and cavities, respectively. The nanoreactors maintain inactive during blood circulation and in normal tissues. Upon accumulation in tumors, the mild acidic microenvironment triggers selective membrane permeability to allow small molecules (glucose and O2) to diffuse across the membrane and react under the catalysis of GOD. The massively generated H2O2 triggers in situ transformation of innocuous prodrugs into toxic parental drugs through cleavage of the self-immolative degradable caging groups. The developed system showed significantly enhanced antitumor efficacy by H2O2 production and prodrug activation via combined oxidation-chemotherapy. The well-devised polymersome nanoreactors with tumor-pH-tunable membrane permeability to coload H2O2-responsive prodrug and GOD represent a novel strategy to realize prodrug delivery and activation for enhanced therapeutic efficacy with low side toxicity.

Keywords: Block copolymer; Cancer therapy; Drug delivery; Nanoreactor; Polymersome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Camptothecin / administration & dosage*
  • Camptothecin / chemistry
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Drug Carriers / administration & dosage*
  • Drug Carriers / chemistry
  • Female
  • Glucose Oxidase / administration & dosage*
  • Glucose Oxidase / chemistry
  • Humans
  • Hydrogen Peroxide / chemistry
  • Hydrogen-Ion Concentration
  • Mice, Inbred ICR
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Oxidation-Reduction
  • Paclitaxel / administration & dosage*
  • Paclitaxel / chemistry
  • Polymers / administration & dosage*
  • Polymers / chemistry
  • Prodrugs / administration & dosage*
  • Prodrugs / chemistry


  • Antineoplastic Agents, Phytogenic
  • Drug Carriers
  • Polymers
  • Prodrugs
  • Hydrogen Peroxide
  • Glucose Oxidase
  • Paclitaxel
  • Camptothecin